A GFD is the only proven treatment for CD. This diet consists in a strict eviction of wheat and its gluten containing derivatives bulgur, couscous and seitan [43], rye, and barley.[63]
Eviction of oat is not so straightforward. In fact, oats contain avenin, a peptid that is similar to gluten and that may elicit a similar immune reaction. Furthermore, oats can induce symptoms as a reaction to an increase in fiber content. As such, gluten-free oat consumption should be restricted to 50-60g/day, patients should be clinically and serologically monitored and oats should be avoided in patients with severe disease.[157]
The amount of gluten patients can tolerate varies. As little as 1/100th of a slice of bread (equivalent to 50 mg of gluten) is sufficient to induce mucosal atrophy. Gluten-free is defined as less than 20 ppm of gluten, the equivalent of 6 mg/day. Less than 10 mg/day seems to be safe.[158, 159]
Due to social and economic constraints or misconceptions concerning GFD, strict adherence to GFD is low, ranging between 17% and 48%.[64, 65] This is of major importance, since mortality seems to increase 5-fold in patients who do not adhere to GFD.[66] An experienced dietician should check for diet compliance regularly.[160]
After starting a GFD, symptoms such as diarrhea, abdominal distension and abdominal pain improve after one month and usually disappear after 6 months.[67] GFD can decrease the risk or improve extra-intestinal manifestations and CD-related conditions. It partially corrects osteopenia, but bone mass seldom returns to normal values.[161]
Most patients become seronegative after 6 months of GFD and only 17% of patients show positive serological tests after 1 year [68, 69], which suggests gluten contamination.[49]
The preferred serological test in the follow-up on GFD is IgA tTG.[70]
Histological normalization takes longer, particularly in adults, in whom it takes 2 to 5 years. [70] A recent study suggested that only 66% of patients who strictly complied to GFD showed total histological recovery after 1 year, which is in contrast with children in whom histological recovery can be expected in 95%.[162]
In addition to classical CD, non-classical CD, seronegative CD, symptomatic PCD, and patients with HD or gluten ataxia also benefit from a GFD. [47] GFD is not recommended for asymptomatic adults with PCD, since only a minority of these patients will develop villous atrophy.[152]
26 GFD should always be lifelong, even if the patient acquires clinical tolerance to gluten.
In fact, about 20% of patients maintain histological remission after gluten reintroduction.
However, histological remission is not a true latency, since those patients tend to present positive serology and IEL, as well as an increased risk for extra-intestinal manifestations and potential for a late relapse.[163]
Several alternative and complementary therapeutics are currently being studied but none showed consistent enough results to be advised in clinical practice. Investigational drugs address different mechanisms of the pathogenesis and include genetically modified less immunogenic wheat strains, prolyl-endopeptidases, non-absorbable polymers with high affinity for gliadin, drugs that decrease intercellular space of enterocytes, drugs that hamper gluten deamination, HLA inhibitor agents, among others.[164]
Patients should be monitored in the first 6 months and then yearly for clinical manifestations, adherence to diet, serology, nutrition and development of associated conditions such as osteoporosis and autoimmune thyroid disease. Laboratorial tests should include anti-tTG IgA, screening for micronutrients deficiency such as full blood count, iron, folic acid, vitamin B12, calcium and vitamin D. Thyroid function and anti-thyroid antibodies may also be considered. [10, 70] Follow-up endoscopy is not routinely advised and should be restricted to patients with persistent or relapsing symptoms despite proper diet. [48] Bone mass should be assessed every 1-2 years in all patients older than 20 years.[43] Lastly, vaccination against pneumococci, Haemophilus influenza and meningococci are strongly recommended.[49]
Complications
RCD occurs in approximately 1.5% of CD cases, and is defined as the persistence of malabsorption signs, symptoms and villous atrophy in patients on GFD for at least a year, when no other causes for villous atrophy or malignancy were identified. [50] The main cause of persistent villous atrophy is inadvertent ingestion of gluten. Other causes should be excluded: lactose intolerance, irritable bowel syndrome, small bowel bacterial overgrowth, pancreatic insufficiency and microscopic colitis.[46]
RCD can be further subclassify in two variants, type I and II, on the bases of phenotype and clonality of IEL. Type I RCD characterizes by normal IEL with polyclonality of the T-cell receptor, whereas type II present aberrant T-cells that lack surface CD8 and CD3 expression, while expressing intracytoplasmatic CD3 and monoclonal T-cell receptor
27 rearrangement. The distinction of these two entities is crucial because treatment and prognosis is different. [43, 165, 166] Type I RCD usually responds to steroids and budesonide or immunomodulators such as azathioprine. Type II RCD is more aggressive, and associates with ulcerative jejunoileitis, severe malabsorption, and high risk of progression to EATL (enteropathy-associated T-cell lymphoma) in 50% of the cases, in 5-10 years [161, 167], with a 5-year survival rate of 44-58%. [161, 166] Type II RCD does not respond to steroids and may require treatment with cladribine or autologous/allogenic bone marrow transplant. Targeting IL-15 is a promising therapeutic strategy.[168]
Patients with CD, especially long-standing and untreated patients, present a higher risk of developing EATL and small intestine adenocarcinoma, when compared to general population. Five-year survival rate for EATL is 11%. The risk for developing other malignancies is still an unanswered topic.[43, 169–171]
Conclusion
CD was described for the first time almost two thousand years ago, however it remains a clinical challenge.
CD presents a wide range of unspecific signs and symptoms, both gastrointestinal and extra-intestinal. Adults tend to be paucisymptomatic, presenting non-classical symptoms, making the diagnosis more difficult. Physicians should use an active case finding strategy, screening patients with suggestive clinical manifestations and those who belong to high-risk groups.
The diagnosis requires highly accurate serological tests and duodenal biopsy with a compatible histopathology. The presence of HLA-DQ2/8 is mandatory for the development of CD and is particularly helpful in uncertain diagnosis. Typical histology findings such as villous atrophy and crypt hyperplasia, are unspecific, which explains the necessity of the other two diagnostic pillars.
The treatment options are scarce being lifelong GFD the only proven treatment for CD, though intense research for different treatment strategies.
28
Agradecimentos
Em primeiro lugar, à Prof. Doutora Mariana Machado, pelas diversas correcções, pela exigência que permitiu elevar este trabalho a um nível superior e, sobretudo, por me ter ajudado a mudar o modo de encarar a investigação científica.
Em seguida aos meus pais. Em particular ao meu pai por ter relido a tese inúmeras vezes e à minha mãe pelo apoio na escolha do curso. Aos dois pelo apoio incondicional ao longo dos últimos 6 anos, por terem feito com que tal fosse possível e por me terem facultado todas as ferramentas necessárias para enfrentar o mundo.
Por fim, mas não menos importante, à Maria, pela paciência na espera deste eterno estudante, pelo companheirismo e pela sua cara alegre quando lhe digo que está quase a acabar.
References
1. Ludvigsson JF, Leffler DA, Bai JC, et al (2013) The Oslo definitions for coeliac disease and related terms. Gut 62:43–52
2. Gee S (1888) On the coeilac affection. St Bartholemews Hosp Rep 24, 17
3. Gasbarrini GB, Mangiola F, Gerardi V, et al (2014) Coeliac disease: An old or a new disease? History of a pathology. Intern Emerg Med 9:249–256
4. Dowd B, Walker-Smith J (1974) Samuel Gee, Aretaeus, and the Coeliac Affection.
Br Med J 2:442
5. Singh P, Arora A, Strand TA, et al (2018) Global Prevalence of Celiac Disease:
Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 16:823-836.e2 6. Mustalahti K, Catassi C, Reunanen A, et al (2010) The prevalence of celiac disease in Europe: Results of a centralized, international mass screening project. Ann Med 42:587–595
7. Lionetti E, Gatti S, Pulvirenti A, et al (2015) Celiac disease from a global perspective. Best Pract Res Clin Gastroenterol 29:365–379
8. Leonard MM, Sapone A, Catassi C, et al (2017) Celiac disease and nonceliac gluten sensitivity: A review. JAMA - J Am Med Assoc 318:647–656
29 9. McAllister BP, Williams E, Clarke K (2018) A Comprehensive Review of Celiac
Disease/Gluten-Sensitive Enteropathies. Clin Rev Allergy Immunol 1–18 10. Lebwohl B, Sanders DS, Green PHR (2018) Coeliac disease. Lancet 391:70–81 11. Dias JA (2017) Celiac Disease: What Do We Know in 2017? GE Port J
Gastroenterol 24:275–278
12. Vriezinga SL, Auricchio R, Bravi E, et al (2014) Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med 371:1304–1315
13. Aronsson CA, Lee HS, Liu E, et al (2015) Age at gluten introduction and risk of celiac disease. Pediatrics 135:239–245
14. Lionetti E, Castellaneta S, Francavilla R, et al (2014) Introduction of gluten, HLA status, and the risk of celiac disease in children. N Engl J Med 371:1295–1303 15. Szajewska H, Shamir R, Chmielewska A, et al (2015) Systematic review with
meta-analysis: Early infant feeding and coeliac disease-update 2015. Aliment Pharmacol Ther 41:1038–1054
16. Szajewska H, Shamir R, Mearin L, et al (2016) Gluten introduction and the risk of coeliac disease: A position paper by the european society for pediatric gastroenterology, hepatology, and nutrition. J Pediatr Gastroenterol Nutr 62:507–
513
17. Mearin ML (2015) The prevention of coeliac disease. Best Pract Res Clin Gastroenterol 29:493–501
18. Stene LC, Honeyman MC, Hoffenberg EJ, et al (2006) Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: A longitudinal study. Am J Gastroenterol 101:2333–2340
19. Ludvigsson JF, Murray JA (2019) Epidemiology of Celiac Disease. Gastroenterol Clin North Am 48:1–18
20. Nellikkal SS, Hafed Y, Larson JJ, et al (2019) High Prevalence of Celiac Disease Among Screened First-Degree Relatives. Mayo Clin Proc 94:1807–1813
21. Pham-Short A, Donaghue KC, Ambler G, et al (2015) Screening for celiac disease in type 1 diabetes: A systematic review. Pediatrics 136:e170–e176
30 22. Elli L, Bonura A, Garavaglia D, et al (2012) Immunological comorbity in coeliac disease: Associations, risk factors and clinical implications. J Clin Immunol 32:984–990
23. Meini A, Pillan NM, Villanacci V, et al (1996) Prevalence and diagnosis of celiac disease in IgA-deficient children. Ann Allergy, Asthma Immunol 77:333–336 24. Carnicer J, Farré C, Varea V, et al (2001) Prevalence of coeliac disease in Down’s
syndrome. 263–267
25. Marild K, Størdal K, Hagman A, et al (2016) Turner syndrome and celiac disease:
A case-control study. Pediatrics 137:
26. Guandalini S, Assiri A (2014) Celiac disease: A review. JAMA Pediatr 168:272–
278
27. Kagnoff MF (2005) Overview and pathogenesis of celiac disease.
Gastroenterology 128:10–18
28. Balakireva A V., Zamyatnin AA (2016) Properties of gluten intolerance: Gluten structure, evolution, pathogenicity and detoxification capabilities. Nutrients 8:
29. Shan L, Molberg Ø, Parrot I, et al (2002) Structural basis for gluten intolerance in Celiac Sprue. Science (80- ) 297:2275–2279
30. Stamnaes J, Sollid LM (2015) Celiac disease: Autoimmunity in response to food antigen. Semin Immunol 27:343–352
31. Parzanese I, Qehajaj D, Patrinicola F, et al (2017) Celiac disease: From pathophysiology to treatment. World J Gastrointest Pathophysiol 8:27
32. Lammers KM, Lu R, Brownley J, et al (2008) Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3. Gastroenterology 135:194–204
33. Rescigno M, Sabatino A Di (2009) Dendritic cells in intestinal homeostasis and disease. Clin Invest 119:2441–2450
34. Xia J, Sollid LM, Khosla C (2005) Equilibrium and kinetic analysis of the unusual binding behavior of a highly immunogenic gluten peptide to HLA-DQ2.
Biochemistry 44:4442–4449
31 35. Du Pré MF, Sollid LM (2015) T-cell and B-cell immunity in celiac disease. Best
Pract Res Clin Gastroenterol 29:413–423
36. Jabri B, Sollid LM (2009) Tissue-mediated control of immunopathology in coeliac disease. Nat Rev Immunol 9:858–870
37. Pender SL, Tickle SP, Docherty AJ, et al (1997) A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol 158:1582–90
38. Bajaj-Elliott M, Poulsom R, Pender SLF, et al (1998) Interactions between stromal cell-derived keratinocyte growth factor and epithelial transforming growth factor in immune-mediated crypt cell hyperplasia. J Clin Invest 102:1473–1480
39. Sollid LM, Molberg, Mcadam S, et al (1997) Autoantibodies in coeliac disease:
Tissue transglutaminase guilt by association? Gut 41:851–852
40. Fernández A, González L, de-la-Fuente J (2010) Coeliac disease: Clinical features in adult populations. Rev Esp Enfermedades Dig 102:466–471
41. Laurikka P, Nurminen S, Kivelä L, et al (2018) Extraintestinal manifestations of celiac disease: Early detection for better long-term outcomes. Nutrients 10:1–14 42. Downey L, Houten R, Murch S, et al (2015) Recognition, assessment, and
management of coeliac disease: Summary of updated NICE guidance. BMJ 351:1–
5
43. Elli L, Ferretti F, Orlando S, et al (2018) Management of celiac disease in daily clinical practice. Eur J Intern Med 61:15–24
44. Kowalski K, Mulak A, Jasiñska M, et al (2017) Diagnostic challenges in celiac disease. Adv Clin Exp Med 26:729–737
45. Schyum AC, Rumessen JJ (2013) Serological testing for celiac disease in adults.
United Eur Gastroenterol J 1:319–325
46. Al-Toma A, Volta U, Auricchio R, et al (2019) European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur Gastroenterol J 7:583–613
47. Lau MSY, Sanders DS (2017) Optimizing the diagnosis of celiac disease. Curr Opin Gastroenterol 33:173–180
32 48. Rubio-Tapia A, Hill ID, Kelly CP, et al (2013) ACG clinical guidelines: Diagnosis
and management of celiac disease. Am J Gastroenterol 108:656–676
49. Husby S, Koletzko S, Korponay-Szabó IR, et al (2012) European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 54:136–160
50. Ludvigsson JF, Bai JC, Biagi F, et al (2014) Diagnosis and management of adult coeliac disease: Guidelines from the British society of gastroenterology. Gut 63:1210–1228
51. McCarty T, O’Brien C, Gremida A, et al (2018) Efficacy of duodenal bulb biopsy for diagnosis of celiac disease: a systematic review and meta-analysis. Endosc Int Open 06:E1369–E1378
52. Oberhuber G (2000) Histopathology of celiac disease. Biomed Pharmacother 54:368–372
53. Sollid LM, Lie BA (2005) Celiac disease genetics: Current concepts and practical applications. Clin Gastroenterol Hepatol 3:843–851
54. Schiepatti A, Sanders DS, Biagi F (2018) Seronegative coeliac disease: Clearing the diagnostic dilemma. Curr Opin Gastroenterol 34:154–158
55. Schiepatti A, Biagi F, Fraternale G, et al (2017) Short article: Mortality and differential diagnoses of villous atrophy without coeliac antibodies. Eur J Gastroenterol Hepatol 29:572–576
56. Volta U, Caio G, Boschetti E, et al (2016) Seronegative celiac disease: Shedding light on an obscure clinical entity. Dig Liver Dis 48:1018–1022
57. Trovato CM, Montuori M, Valitutti F, et al (2019) The Challenge of Treatment in Potential Celiac Disease. Gastroenterol Res Pract 2019:1–6
58. Volta U, Caio G, De Giorgio R, et al (2015) Non-celiac gluten sensitivity: A work-in-progress entity in the spectrum of wheat-related disorders. Best Pract Res Clin Gastroenterol 29:477–491
59. Catassi C, Elli L, Bonaz B, et al (2015) Diagnosis of non-celiac gluten sensitivity (NCGS): The salerno experts’ criteria. Nutrients 7:4966–4977
33 60. Schuppan D, Pickert G, Ashfaq-Khan M, et al (2015) Non-celiac wheat sensitivity:
Differential diagnosis, triggers and implications. Best Pract Res Clin Gastroenterol 29:469–476
61. Volta U, Tovoli F, Cicola R, et al (2012) Serological tests in gluten sensitivity (nonceliac gluten intolerance). J Clin Gastroenterol 46:680–685
62. Mansueto P, Seidita A, D’Alcamo A, et al (2014) Non-Celiac Gluten Sensitivity:
Literature Review. J Am Coll Nutr 33:39–54
63. Bascuñán KA, Vespa MC, Araya M (2017) Celiac disease: understanding the gluten-free diet. Eur J Nutr 56:449–459
64. Leffler DA, Edwards-George J, Dennis M, et al (2008) Factors that influence adherence to a gluten-free diet in adults with celiac disease. Dig Dis Sci 53:1573–
1581
65. Hall NJ, Rubin G, Charnock A (2009) Systematic review: Adherence to a gluten-free diet in adult patients with coeliac disease. Aliment Pharmacol Ther 30:315–
330
66. Corrao G, Corazza GR, Bagnardi V, et al (2001) Mortality in patients with coeliac disease and their relatives: a cohort study. 358:356–361
67. Oxentenko AS, Murray JA (2015) Celiac Disease: Ten Things That Every Gastroenterologist Should Know. Clin. Gastroenterol. Hepatol. 13:
68. Zanini B, Lanzarotto F, Mora A, et al (2010) Five year time course of celiac disease serology during gluten free diet: Results of a community based “ CD-Watch”
program. Dig Liver Dis 42:865–870
69. Rashid M, Lee J (2016) Serologic testing in celiac disease Practical guide for clinicians. Can Fam Physician 62:38–43
70. Mulder CJ, Wierdsma NJ, Berkenpas M, et al (2015) Preventing complications in celiac disease: Our experience with managing adult celiac disease. Best Pract Res Clin Gastroenterol 29:459–468
71. Freeman HJ (2015) Celiac disease: A disorder emerging from antiquity, its evolving classification and risk, and potential new treatment paradigms. Gut Liver
34 9:28–37
72. Herter CA (1909) On Infantilism from Chronic Intestinal Infection, characterized by the Overgrowth and Persistence of Flora of the Nursling Period. Bost Med Surg J 160:416
73. Yan D, Holt PR (2009) Willem Dicke. Brilliant clinical observer and translational investigator. discoverer of the toxic cause of celiac disease. Clin Transl Sci 2:446–
448
74. Haas SV (1924) The value of the banana in the treatment of coeliac disease. Am J Dis Child 24:421–437
75. Van Berge-Henegouwen GP, Mulder CJJ (1993) Pioneer in the gluten free diet:
Willem-Karel Dicke 1905-1962, over 50 years of gluten free diet. Gut 34:1473–
1475
76. Paulley JW (1954) Observations on the aetiology of idiopathic steatorrhoea:
Jejunal and lymph-node biopsies. Br Med J 2:1318–1325
77. Berger E, Burgin-Wolff A, Freudenberg E (1964) Diagnostisehe Bewertung des Nachweises yon Gliadin-AntikSrpern bei Ciiliakie Von. 788–790
78. Kilander AF, Dotevall G, Fällström SP, et al (1983) Evaluation of gliadin antibodies for detection of coeliac disease. Scand J Gastroenterol 18:377–383 79. Signer E, Bürgin-Wolff A, Berger R, et al (1979) Antibodies to gliadin as a
screening test for coeliac disease. A prospective study. Helv Paediatr Acta 34:41–
52
80. Chorzelski TP, Beutner EH, Sulej J, et al (1984) IgA anti‐endomysium antibody.
A new immunological marker of dermatitis herpetiformis and coeliac disease. Br J Dermatol 111:395–402
81. Dieterich W, Ehnis T, Bauer M, et al (1997) Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 4:303–308
82. Falchuk ZM, Rogentine GN, Strober W (1972) Predominance of histocompatibility antigen HLA-8 in patients with gluten-sensitive enteropathy. J Clin Invest 51:1602–1605
35 83. Wagener P (2007) A Brief History of Celiac Disease. Univ Chicago Celiac Dis
Cent 7:1–4
84. Husby S, Koletzko S, Korponay-Szabó I, et al (2020) European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr 70:141–156
85. West J, Fleming KM, Tata LJ, et al (2014) Incidence and prevalence of celiac disease and dermatitis herpetiformis in the UK over two decades: Population-based study. Am J Gastroenterol 109:757–768
86. Greco L, Romino R, Coto I, et al (2002) The first large population based twin study of coeliac disease. Gut 50:624–628
87. Nisticò L, Fagnani C, Coto I, et al (2006) Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut 55:803–804
88. Withoff S, Li Y, Jonkers I, et al (2016) Understanding Celiac Disease by Genomics. Trends Genet 32:295–308
89. Fewtrell M, Bronsky J, Campoy C, et al (2017) Complementary feeding: A position paper by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) committee on nutrition. J Pediatr Gastroenterol Nutr 64:119–132
90. Silano M, Agostoni C, Sanz Y, et al (2016) Infant feeding and risk of developing celiac disease: A systematic review. BMJ Open 6:
91. Pinto-Sánchez MI, Verdu EF, Liu E, et al (2016) Gluten Introduction to Infant Feeding and Risk of Celiac Disease: Systematic Review and Meta-Analysis. J Pediatr 168:132-143.e3
92. Weile B, Cavell B, Nivenius K, et al (1995) Striking Differences in the Incidence of Childhood Celiac Disease Between Denmark and Sweden. J Pediatr Gastroenterol Nutr 21(1):64–68
93. Singh P, Arora S, Lal S, et al (2015) Risk of celiac disease in the first- and second-degree relatives of patients with celiac disease: A systematic review and meta-analysis. Am J Gastroenterol 110:1539–1548
36 94. Fasano A, Berti I, Gerarduzzi T, et al (2003) Prevalence of Celiac Disease in
At-Risk and Not-At-At-Risk Groups in the United States. Arch. Intern. Med. 163:
95. Kagnoff MF (2007) Celiac disease : pathogenesis of a model immunogenetic disease. J Clin Invest 117:41–49
96. Sollid LM (2017) The roles of MHC class II genes and post-translational modification in celiac disease. Immunogenetics 69:605–616
97. Karinen H, Kärkkäinen P, Pihlajamäki J, et al (2006) Gene dose effect of the DQB1*0201 allele contributes to severity of coeliac disease. Scand J Gastroenterol 41:191–199
98. Caio G, Volta U, Sapone A, et al (2019) Celiac disease: A comprehensive current review. BMC Med 17:1–20
99. Reunala T, Salmi TT, Hervonen K, et al (2018) Dermatitis herpetiformis: A common extraintestinal manifestation of coeliac disease. Nutrients 10:1–9
100. Pellegrini FP, Marinoni M, Frangione V, et al (2012) Down syndrome, autoimmunity and T regulatory cells. Clin Exp Immunol 169:238–243
101. Kahaly GJ, Frommer L, Schuppan D (2018) Celiac disease and endocrine autoimmunity – the genetic link. Autoimmun Rev 17:1169–1175
102. Rodrigues F, Bachmeyer C (2018) Coeliac disease and dermatitis herpetiformis.
Lancet 392:916
103. Sørensen HT, Thulstrup AM, Blomqvist P, et al (1999) Risk of primary biliary liver cirrhosis in patients with coeliac disease: Danish and Swedish cohort data.
Gut 44:736–738
104. Ludvigsson JF, Elfström P, BroomÉ U, et al (2007) Celiac Disease and Risk of Liver Disease: A General Population-Based Study. Clin Gastroenterol Hepatol 5:63–69
105. Mearns ES, Taylor A, Thomas Craig KJ, et al (2019) Neurological manifestations of neuropathy and ataxia in celiac disease: A systematic review. Nutrients 11:380 106. Hadjivassiliou M, Sanders DD, Aeschlimann DP (2015) Gluten-related disorders:
Gluten ataxia. Dig Dis 33:264–268
37 107. Bushara KO (2005) Neurologic presentation of celiac disease. Gastroenterology
128:92–97
108. Freeman HJ (2008) Neurological disorders in adult celiac disease. Can J Gastroenterol 22:909–911
109. Hadjivassiliou M, Rao DG, Grìnewald RA, et al (2016) Neurological dysfunction in coeliac disease and non-coeliac gluten sensitivity. Am J Gastroenterol 111:561–
567
110. Korponay-Szabó IR, Dahlbom I, Laurila K, et al (2003) Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency. Gut 52:1567–1571
110. Korponay-Szabó IR, Dahlbom I, Laurila K, et al (2003) Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency. Gut 52:1567–1571